Ruthenium-catalyzed ortho-selective aromatic CH alkenylation with alkenyl carbonates

Article abstract of DOI:10.1246/cl.140006

Ortho-selective aromatic CH alkenylation with alkenyl carbonates proceeds in the presence of a catalytic amount of [Ru(cod)(cot)]. Arylpyridines and an aryloxazoline were regioselectively alkenylated without adding external bases. Aromatic CH alkylation also occurs depending on the reaction conditions.

Full text of DOI:10.1246/cl.140006

Received: January 3, 2014 | Accepted: January 20, 2014 | Web Released: May 5, 2014
CL-140006
Ruthenium-catalyzed Ortho-selective Aromatic C-H Alkenylation
with Alkenyl Carbonates
Yohei Ogiwara,1 Takuya Kochi,1 and Fumitoshi Kakiuchi*1,2
1Department of Chemistry, Faculty of Science and Technology, Keio University,
3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522
2JST, Advanced Catalytic Transformation program for Carbon utilization (ACT-C),
4-1-8 Kawaguchi, Honcho, Saitama 332-0012
(E-mail: kakiuchi@chem.keio.ac.jp)
Ortho-selective aromatic C-H alkenylation with alkenyl
carbonates proceeds in the presence of a catalytic amount of
[Ru(cod)(cot)]. Arylpyridines and an aryloxazoline were regio-
selectively alkenylated without adding external bases. Aromatic
C-H alkylation also occurs depending on the reaction conditions.
out any further additives to afford ortho-alkenylation products
from aromatic compounds, including arylpyridines and an
aryloxazoline. Depending on the reaction conditions, alkylation
products can also be prepared.
When o-tolylpyridine 2a was reacted with 3 equiv of ethyl β-
styryl carbonate (1a) in the presence of 5 mol % of [Ru(cod)(cot)]
for 24 h in gently refluxing p-xylene by heating in an oil bath
whose temperature was adjusted to 150 °C, ortho-alkenylation
product 3a was obtained in 51% yield, along with alkylation
product 4a in 2% yield (Table 1, Entry 1). The product yield was
improved to 71% by using 10 mol % of the catalyst and 5 equiv
of 1a (Entry 2). The reaction of 2a and 3 equiv of isopropyl β-
styryl carbonate (1b) with 5 mol % of [Ru(cod)(cot)] afforded
70% yield of alkenylation product 3a, but the yield of alkylation
product 4a was also increased to 3% (Entry 3). Examination of
the reaction conditions revealed that the reaction with 5 equiv
of 1b for 48 h afforded product 3a in 90% yield (Entry 4). When
the reaction was performed on gram-scale (5 mmol of 2a), 1.12 g
(83%) of 3a was isolated (Entry 5). The use of methyl, tert-butyl,
or phenyl carbonate for alkenylation was not effective and
afforded low yields of alkenyltion product 3a (Entries 6-8).
Examination of the C-H alkenylation reaction of several
arylpyridines was conducted under the conditions described for
Entries 2 (conditions A, using carbonate 1a) and 4 (conditions
B, using carbonate 1b) in Table 1 (Table 2). The alkenylation of
Catalytic alkenylation of C-H bonds is a powerful method
for the synthesis of styrene derivatives, which can be found in
many molecules of biological, pharmaceutical, and industrial
interest. There have been several classes of methods developed
for catalytic aromatic C-H alkenylation,1 and one of them is
coupling with alkenes bearing halides or pseudohalides as
leaving groups (Scheme 1a).2-7 This class of alkenylation
enables the introduction of various types of alkenyl groups by
designing appropriate alkenes with leaving groups. However, it
produces the corresponding acid originating from the leaving
group such as hydrogen halides, and in most cases, addition of a
base is necessary to conduct the reaction.
In this context, our group developed aromatic C-H
alkenylation with alkenyl esters using ruthenium catalysts.8
This reaction provides alkenylation products along with carbox-
ylic acids such as acetic acid as by-products. The acidity of the
carboxylic acids is weak enough to perform the reaction without
adding a base for most of the substrates, including arylpyridines,
but more basic substrates such as oxazolines require the addition
of 2,6-lutidine to scavenge the acid by-product. In search of an
alkenylation reaction under more neutral conditions, we envi-
sioned the use of alkyl alkenyl carbonates 1 as alkenylating
agents, because the leaving group, alkylcarbonate, may degrade
into carbon dioxide and the corresponding alkoxide, which
eventually affords an alcohol as a by-product (Scheme 1b).
Here, we describe a catalytic aromatic C-H alkenylation
using alkenyl carbonates. The reaction was catalyzed by
[Ru(cod)(cot)] (cod: cyclooctadiene, cot: cyclooctatriene) with-
Table 1. Ruthenium-catalyzed C-H alkenylation of arylpyri-
dine 2a with alkenylcarbonates 1a
cat.
O
N
N
N
[Ru(cod)(cot)]
Ph
+
+
RO
O
Ph
Ph
p-xylene
reflux
(oil bath temp
150 °C)
E:Z = 5:5-7:3
2a
1
3a
4a
1
Yields/%b
[Ru(cod)(cot)]
Time
/h
Entry
/mol %
R
equiv
3a
4a
a)
1
2
3
4
5c
6
7
8
5
10
5
5
5
5
5
5
Et (1a)
Et
i-Pr (1b)
i-Pr
3
5
3
5
5
3
3
3
24
24
24
48
48
24
24
24
51
71
70
90
83d
2
2
3
3
®
DG
DG
H
H
R2
catalyst
R2
+
+
+
+
HX
R1
b)
R1
R1
X
i-Pr
DG
DG
O
Me (1c)
t-Bu (1d)
Ph (1e)
11 nde
23 nde
R2
catalyst
R2
CO2
+
HOR3
R3O
O
R1
1
8
nde
aConditions: 2a (0.5 mmol), 1, [Ru(cod)(cot)], p-xylene
Scheme 1. Catalytic C-H alkenylations of aromatic com-
pounds with (a) alkenyl halides and pseudohalides and with
(b) carbonates.
b
c
(0.1 mL), reflux (oil bath temp 150 °C). GC yields. 5 mmol
d
e
scale. Isolated yield. Not detected.
Chem. Lett. 2014, 43, 667–669 | doi:10.1246/cl.140006
© 2014 The Chemical Society of Japan | 667

Table 2. Ruthenium-catalyzed C-H alkenylation of aromatic
compounds with alkenylcarbonates 1a
monoalkenylation product 3e in lower yields (Entries 7 and 8),
and under conditions A, product 3e was obtained in 50% yield
(Entry 7).
DG
DG
O
cat. [Ru(cod)(cot)]
Ph
+
C-H alkenylation was also investigated with o-tolyloxazo-
line 2f, whose alkenylation using alkenyl acetate requires
addition of a base, 2,6-lutidine, to obtain the alkenylation
product in good yield (69%) because of the relatively high
basicity of the oxazoline ring.8 To examine if the reaction of 2f
with alkenyl carbonates proceeds without addition of a base
because it affords alcohols as by-products, the alkenylation was
performed under conditions A and B and indeed proceeded to
afford 77% yield of the corresponding alkenylation product 3f in
each case (Entries 9 and 10). In addition to alkenylation products
3, small amounts of the corresponding alkylation products, 4b-
4f, were also detected by GC and GC-MS for all entries in
Table 2.
The reaction of 2a with isopropyl β-styryl carbonate (1b)
was also examined to investigate if alkylation product 4a can be
obtained as the major product, and it turned out that harsh
refluxing conditions facilitated the alkylation reaction and the
reaction at 170 °C (oil bath temperature) afforded 62% GC yield
of alkylation product 4a, which was isolated in 45% yield, along
with alkenylation product 3a in 11% GC yield (eq 1).
Ph
R1
RO
O
R1
p-xylene, reflux
(oil bath temp 150 °C)
2
1
3
GC yield
/%
Entry
1
2
Conditions
A
3
82
43
80
85
63
54
50
25
N
N
Ph
2
3
4
5
6
7
8
B
A
B
A
B
A
B
2b
2c
2d
2e
3b
N
N
F3C
F3C
Ph
3c
N
N
Ph
5 mol %
[Ru(cod)(cot)]
O
N
N
N
Ph
+
+
ð1Þ
iPrO
O
Ph
Ph
p-xylene
reflux
(oil bath temp
3d
3 equiv
2a
1b
3a
11% GC yield
4a
170 °C)
62% GC yield
(45% isolated yield)
N
N
If C-H alkenylation using alkenyl carbonates proceeds in a
similar manner to alkenyl esters,8b a plausible mechanism is
shown in Figure 1.9 That is, oxidative addition of the ortho C-H
bond and hydrometalation of alkenyl carbonate are followed
by β-alkoxycarboxy elimination to afford olefin complex A.
Carbometalation (step a) and β-hydride elimination (step b) then
lead to the formation of alkenylation product 3a. It is not clear at
which point decarboxylation occurs, but this process transforms
the alkoxycarboxy group into the alkoxy group. The alkoxy
intermediates may undergo β-hydride elimination to afford
hydrides B and C, which can be used to produce alkylation
product 4a by either reductive elimination after carbometalation
(step a or c) or hydrometalation (step d), or reduction of
alkenylation product 3a (step e).10 The alkylation reaction may
be facilitated by rigorous exclusion of carbon dioxide to assist
the decarboxylation process.
Ph
F3C
F3C
3e
9
A
B
77
77
O
N
O
N
Ph
10
2f
3f
aConditions A: 2 (0.5 mmol), 1a (2.5 mmol), [Ru(cod)(cot)]
(0.05 mmol), p-xylene (0.1 mL), reflux (oil bath temp 150 °C),
24 h; conditions B: 2 (0.5 mmol), 1b (2.5 mmol), [Ru(cod)(cot)]
(0.025 mmol), p-xylene (0.1 mL), reflux (oil bath temp 150 °C),
48 h.
In conclusion, we developed a ruthenium-catalyzed ortho
C-H alkenylation of aromatic compounds with alkenyl carbon-
ates. Arylpyridines were regioselectively alkenylated by ethyl
and isopropyl alkenyl carbonates in the presence of a catalytic
amount of [Ru(cod)(cot)]. An aryloxazoline was also identified
as an effective substrate for alkenylation with alkenyl carbon-
ates. In this case, addition of a base was unnecessary to achieve
high yields, probably because of the low acidity of the alcohol
by-products, in contrast to the previously described reaction with
alkenyl acetates, which requires the addition of 2,6-lutidine.
When the reaction was conducted at 170 °C (oil bath temper-
ature), an alkylation product became the major product.
Mechanistic investigations of C-H alkenylation with alkenyl
carbonates are still underway.
phenylpicoline 2b with carbonate 1a afforded the corresponding
ortho-alkenylation product 3b in 82% yield (Entry 1), and the
reaction under conditions B using carbonate 1b resulted in lower
yield (Entry 2). In the case of arylpyridine 2c bearing a
trifluoromethyl group at the ortho position on the phenyl ring,
high yields of product 3c were obtained for reactions under both
conditions A and B (Entries 3 and 4). Arylpyridines with meta
substituents were also investigated for the alkenylation. For m-
tolylpyridine 2d, the C-H alkenylation took place only at the
less congested ortho position and afforded the corresponding
monoalkenylation product 3d in 63% and 54% yields under
conditions A and B, respectively (Entries 5 and 6). The reaction
of arylpyridine 2e with a m-trifluoromethyl group provided
668 | Chem. Lett. 2014, 43, 667–669 | doi:10.1246/cl.140006
© 2014 The Chemical Society of Japan

Ph
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In the case of the reaction using alkenyl acetate as an
alkenylating agent, the Z-isomer reacted faster than the E-
isomer (See ref 8b). Although the difference in reactivity
between E- and Z-carbonate 1 is not clear, when the reaction
was performed using 1b (Table 1, Entry 4), the ratio of the
Z-isomer in the remaining 1b slightly decreased from that of
the starting 1b (E:Z = 32:68 to 36:64).
Ph
Ph
[Ru]
H
[Ru],
N
N
N
OCOOR
[Ru]
O
OCOOR
H
O
OR
2a
Ph
OCOOR
N
N
[Ru]
Ph
N
step b
CO2
step a
[Ru]
Ph
–
–
OCOOR
OR
A
[Ru]
H
3a
step e
–
–
CO2
O
–
CO2
R'
R'
R"
–
O
OR
[Ru]
R'
R"
–
O
H
3
4
R"
Ph
H
N
N
[Ru]
step c
[Ru]
Ph
N
H
Ph
C
B
step d
4a
N
Ph
[Ru]
H
OR = O
R'
R"
Figure 1. Proposed mechanisms of the catalytic C-H alkenyl-
ation and the alkylation.
5
6
7
This work was supported, in part, by a Grant-in-Aid for
Scientific Research (No. 21350056) from MEXT and by a Grant
for Private Education Institute Aid from MEXT. Y.O. acknowl-
edges JSPS Research Fellowships for Young Scientists
(No. 4259).
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8
9
10 The reduction of 3a was observed when the reaction of
3a with 2b and 1b was performed in the presence of
[Ru(cot)(cot)] as a catalyst. See the Supporting Information
for details. Supporting Information is available electronically
on the CSJ-Journal Web site, http://www.csj.jp/journals/
chem-lett/index.html.
2
Chem. Lett. 2014, 43, 667–669 | doi:10.1246/cl.140006
© 2014 The Chemical Society of Japan | 669